Sequential changes in vessel formation and micro-vascular function during bone repair.

TY - JOUR

T1 - Sequential changes in vessel formation and micro-vascular function during bone repair.

AU - Hansen-Algenstaedt, Nils

AU - Joscheck, Claudia

AU - Wolfram, Lars

AU - Schäfer, Christian

AU - Müller, Ingo

AU - Böttcher, Antje

AU - Deuretzbacher, Georg

AU - Wiesner, Lothar

AU - Leunig, Michael

AU - Algenstaedt, Petra

AU - Rüther, Wolfgang

PY - 2006

Y1 - 2006

N2 - BACKGROUND: Angiogenesis, the process of new vessel formation from a pre-existing vascular network, is essential for bone development and repair. New vessel formation and microvascular functions are crucial during bone repair, not only for sufficient nutrient supply, transport of macromolecules and invading cells, but also because they govern the metabolic microenvironment. Despite its central role, very little is known about the initial processes of vessel formation and microvascular function during bone repair. METHODS: To visualize and quantify the process of vessel formation and microvascular function during bone repair, we transplanted neonatal femora with a substantial defect into dorsal skin-fold chambers in severe combined immunodeficient (SCID) mice for continuous noninvasive in-vivo evaluation. We employed intravital microscopic techniques to monitor effective microvascular permeability, functional vascular density, blood flow rate and leukocyte flux repeatedly over 16 days. Oxytetracyclin and v. Kossa/v. Giesson staining was performed to quantify the calcification process in vivo and in vitro. RESULTS: Development of a hematoma surrounding the defect area was the initial event, which was accompanied by a significant increase in microvascular permeability and blood flow rate. With absorption of the hematoma and vessel maturation, permeability decreased continuously, while vascular density and tissue perfusion increased. Histological evaluation revealed that the remodeling of the substantial defect prolonged the in-vivo monitored calcification process. INTERPRETATION: The size of the initial substantial defect correlated positively with increased permeability, suggesting improved release of permeability-inducing cytokines. The unchanged permeability in the control group with boiled bones and a substantial defect corroborated these findings. The adaptation to increasing metabolic demands was initially mediated by increased blood flow rate, later with increasing vascular density through increased tissue perfusion rate. These insights into the sequence of microvascular alterations may assist in the development of targeted drug delivery therapies and caution against the use of permeability-altering drugs during bone healing.

AB - BACKGROUND: Angiogenesis, the process of new vessel formation from a pre-existing vascular network, is essential for bone development and repair. New vessel formation and microvascular functions are crucial during bone repair, not only for sufficient nutrient supply, transport of macromolecules and invading cells, but also because they govern the metabolic microenvironment. Despite its central role, very little is known about the initial processes of vessel formation and microvascular function during bone repair. METHODS: To visualize and quantify the process of vessel formation and microvascular function during bone repair, we transplanted neonatal femora with a substantial defect into dorsal skin-fold chambers in severe combined immunodeficient (SCID) mice for continuous noninvasive in-vivo evaluation. We employed intravital microscopic techniques to monitor effective microvascular permeability, functional vascular density, blood flow rate and leukocyte flux repeatedly over 16 days. Oxytetracyclin and v. Kossa/v. Giesson staining was performed to quantify the calcification process in vivo and in vitro. RESULTS: Development of a hematoma surrounding the defect area was the initial event, which was accompanied by a significant increase in microvascular permeability and blood flow rate. With absorption of the hematoma and vessel maturation, permeability decreased continuously, while vascular density and tissue perfusion increased. Histological evaluation revealed that the remodeling of the substantial defect prolonged the in-vivo monitored calcification process. INTERPRETATION: The size of the initial substantial defect correlated positively with increased permeability, suggesting improved release of permeability-inducing cytokines. The unchanged permeability in the control group with boiled bones and a substantial defect corroborated these findings. The adaptation to increasing metabolic demands was initially mediated by increased blood flow rate, later with increasing vascular density through increased tissue perfusion rate. These insights into the sequence of microvascular alterations may assist in the development of targeted drug delivery therapies and caution against the use of permeability-altering drugs during bone healing.

U2 - 10.1080/17453670610046361

DO - 10.1080/17453670610046361

M3 - SCORING: Zeitschriftenaufsatz

VL - 77

SP - 429

EP - 439

JO - ACTA ORTHOP

JF - ACTA ORTHOP

SN - 1745-3674

IS - 3

M1 - 3

ER -